Assessment of the CYP3A-Mediated Drug Interaction Potential of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Volunteers
| Autor: | Arthur J. Bergman, John A. Wagner, James Dru, Brad Roadcap, Rajesh Krishna, Josee Cote, Eva Vets, Rita Chiou, Amit Garg, Regina W. Wang, Bo Jin, Varsha Didolkar, T Laethem, Keith Gottesdiener |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Adolescent Midazolam Cmax In Vitro Techniques Pharmacology Young Adult chemistry.chemical_compound Cytochrome P-450 Enzyme System Pharmacokinetics Anacetrapib Cholesterylester transfer protein medicine Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Humans Drug Interactions Pharmacology (medical) CETP inhibitor Oxazolidinones biology Chemistry Middle Aged Drug interaction Cholesterol Ester Transfer Proteins Ketoconazole Tolerability Hepatocytes Microsomes Liver biology.protein medicine.drug |
| Zdroj: | The Journal of Clinical Pharmacology. 49:80-87 |
| ISSN: | 0091-2700 |
| Popis: | In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A. |
| Databáze: | OpenAIRE |
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